Regulation of Glioblastoma Stem-Like Cells by CDC20-Anaphase-Promoting Complex

摘要 胶质母细胞瘤是成人最常见的恶性原发脑肿瘤，通常是致命的。胶质母细胞瘤 干细胞样细胞(GSCs)代表胶质母细胞瘤细胞的动态亚群，目前已知 表现出治疗耐药性，并导致肿瘤复发。因此，对治理机制的了解 GSC状态对于开发有效的治疗胶质母细胞瘤是必不可少的。使用患者派生的 胶质母细胞瘤细胞系，我们最近发现了一种对E3连接酶CDC20-后期的需求- 促进复合体(CDC20-APC)在GSC侵袭、自我更新和肿瘤启动等关键功能中的作用。 此外，我们还鉴定了多能调控转录因子SOX2是一种新的CDC20- 相互作用蛋白，在体外介导CDC20-APC在GSCs中的下游作用。究竟是如何 CDC20-APC/SOX2信号通路在神经干细胞中的调控及其作用 胶质母细胞瘤在体内的作用尚不明确。我们建议的目标是：1)识别分子 CDC20-APC/SOX2通路在GSC侵袭性中的潜在机制，2)确定 CDC20-APC/SOX2通路在胶质母细胞瘤体内启动和维持中的作用 确定CDC20-APC/SOX2通路对GSC对标准护理的反应性的影响 化疗、替莫唑胺和放射治疗。这个项目的长期目标是开发新的 CDC20-APC指导的破坏GSC状态和增强电流疗效的治疗策略 治疗。

ABSTRACT Glioblastoma is the most common malignant primary brain tumor in adults and is invariably fatal. Glioblastoma stem-like cells (GSCs) represent a dynamic subpopulation of glioblastoma cells, which are now known to exhibit treatment resistance and cause tumor recurrence. Therefore, knowledge of the mechanisms governing the GSC state is essential to develop effective therapies against glioblastoma. Using patient-derived glioblastoma cell lines, we have recently uncovered a requirement for the E3 ligase CDC20-Anaphase- Promoting Complex (CDC20-APC) in key GSC functions of invasion, self-renewal, and tumor initiation. Furthermore, we have identified the pluripotency regulatory transcription factor SOX2 as a novel CDC20- interacting protein, which mediates the downstream effects of CDC20-APC in GSCs in vitro. How exactly the CDC20-APC/SOX2 signaling pathway is regulated in GSCs and what role the CDC20-APC/SOX2 pathway plays in glioblastoma in vivo remain to be defined. The goals of our proposal are: 1) to identify the molecular mechanisms underlying the CDC20-APC/SOX2 pathway in GSC invasiveness, 2) to determine the impact of the CDC20-APC/SOX2 pathway on tumor initiation and maintenance in glioblastoma in vivo, and 3) to determine the effect of the CDC20-APC/SOX2 pathway on GSC responsiveness to standard-of-care chemotherapy temozolomide and radiation therapy. The long-term goal of this project is to develop novel CDC20-APC-directed therapeutic strategies to disrupt the GSC state and enhance the effectiveness of current treatments.